The amino acid L-glutamate (which herein is referred to simply as glutamate) is the principal excitatory neurotransmitter in the brain and other elements of the central nervous system of mammals. Glutamate binds to neurons and activates cell surface receptors. Glutamate has significant roles in motor control, cognitive function, sensory perception, and acts as a mediator of persistent changes in the strength of synaptic signaling (synaptic plasticity), thereby modulating long term potentiation (LTP) and long term depression (LTD), which form the basis of learning and memory. Many neurological and neuropsychiatric disorders, including, but not limited to, psychosis spectrum disorders, schizophrenia and other cognitive deficits, are associated with aberrations in the function of (or the regulation by, or the regulation of) glutamate signaling systems.
Glutamate acts through two heterogeneous families of receptors: ionotropic and metabotropic glutamate receptors (mGluR). mGluRs are G protein-coupled receptors that activate intracellular second messengers when bound to glutamate. Eight subtypes of mGluRs have been cloned and classified into three groups on the basis of sequence similarities and pharmacological properties. mGluR1 and mGluR5 belong to Group I, which initiate cellular responses through a G-protein mediated mechanism and activate phospholipase C, leading to phosphoinositide hydrolysis and the mobilization of intracellular calcium (Schoepp, D. D., et al., Neuropharmacology 1999, 38, 1431). Two receptors that are central to the current understanding of new approaches for the treatment of the foregoing neurological and neuropsychiatric disorders are (i) an ionotropic glutamate receptor, namely the NMDA receptor [reviewed in Stahl, S. M. (2007) CNS Spectrum 12: 583-588], and (ii) mGluR5 [reviewed in Lindsley, C. W. et al. (2006) Current Topics in Medicinal Chemistry 6: 771-885; Pietraszek, M. et al. (2007) Amino Acids 32: 173-178]. A salient aspect of this understanding is that reduced function (hypofunction) of the NMDA receptor is involved in the symptoms of psychotic and schizophrenic diseases and disorders [Stahl, S. M. (2007) CNS Spectrum 12: 583-588]. Since activation of mGluR5 causes activation of the NMDA receptors that are present post-synaptically in the same cells, the exposure of the CNS to a positive allosteric modulator of mGluR5 may lead to increases in neuronal ion currents (and increased synaptic circuit firing) dependent upon the NMDA receptor [Lecourtier, L. et al. (2007) Biological Psychiatry 62:739-746; Uslaner, J. M. et al. (2009) Neuropharmacology 57: 531-538], as well as to behavioral changes that may indicate antipsychotic and pro-cognitive activities [Liu, F. et al. (2008) J. Pharmacol. Exp. Ther. 327: 827-839; Kinney, G. G. et al. (2005) J. Pharmacol. Exp. Ther. 313: 199-206]. Positive allosteric modulators of mGluR5 therefore may be of benefit in the treatment of psychotic, schizophrenic, cognitive and related neurological and neuropsychiatric diseases, either alone, or as adjunctive therapies combined with other treatments.
Moreover, since mGluR5 is expressed in both the central nervous system and the periphery (Chizh, B. A., et al., Amino Acids 2002, 23, 169), modulation of mGluR5 activity may be useful in the treatment of both peripheral and CNS disorders. With respect to peripheral disorders, mGluR5 negative allosteric modulators have shown efficacy in the treatment of gastrointestinal (GI) tract disorders, such as gastroesophageal reflux disease (GERD).
In the CNS, excessive activation of mGluR5 has been implicated in a number of diseases, such as various pain states, neuropsychiatric disorders such as anxiety and depression, and other neurological impairments such as drug addiction and drug withdrawal. For example, mGluR5 negative allosteric modulators are efficacious in the treatment of anxiety in a variety of animal models, including stress-induced hyperthermia and fear-potentiated startle.
Migraine is another CNS disorder relevant to mGluR5 modulation. Migraine is a chronic debilitating condition characterized by recurrent severe headaches that are often accompanied by a variety of other symptoms, such as nausea and fatigue. Pharmacologic therapies for the treatment of migraine may be divided into two classes, acute therapies for the treatment of symptoms when they arise, and chronic therapies designed to prevent the onset of migraine (prophylactics) (Goadsby, P. J., et al., N. Engl. J. Med. 2002, 346, 257). The best known therapeutics for the treatment of acute migraine are triptans, dual 5-HT1b/5-HT1d agonists that exert their therapeutic effects through cranial vasoconstriction. Although generally well-tolerated, their use is restricted in the presence of cardiovascular disease due to their 5-HT1b agonism.
In contrast to the treatment for acute attacks, the current therapies for migraine prophylaxis may be subdivided into three classes: β-blockers, anticonvulsants, and antidepressants. All are moderately effective and carry substantial side-effects. Most prominent among the β-blockers is propranolol, whose side-effects include lethargy and hypotension. Valproate and topiramate are the most commonly used anticonvulsants, but, like the antidepressants, they cause side-effects such as fatigue. There is a clear medical need for a novel prophylactic therapy that is effective and free from the side-effects. Recently, an mGluR5 antagonist demonstrated efficacy in treating acute migraine in human clinical trials. The robust anxiolytic and antidepressant activities of mGluR5 antagonists should be beneficial to migraine patients, who often suffer anxiety and depression.
Other peripheral and CNS disorders relevant to mGluR5 modulation include schizophrenia, neurodegenerative diseases, levodopa-induced dyskinesia, fragile X syndrome, substance abuse/addiction, epilepsy, inflammatory, visceral and neuropathic pain, and post-traumatic stress disorder. Therefore, there is a need for effective mGluR5 modulators as therapeutics for the treatment of the aforementioned disorders.